DISCUSSION
The present study is the first large-scale evaluation of COVID-19 symptomatology in patients with moderate-to-severe AD, aiming to understand the effect of specific Th2 modulation with dupilumab compared with other systemic immunomodulators and to topical or no treatment. Understanding COVID-19 symptomatology in patients with moderate-to-severe AD in the context of immunomodulatory treatment is crucial, due to the long-term health consequences of SARS-CoV-2 infection, which are more substantial with moderate-to-severe symptomatology,33 as well as the massive economic burden on the United States hospital system from treating COVID-19 patients.34 Patients with moderate-to-severe AD are also particularly important to study in this context due to their increased susceptibility to viral infections and their robust Type 2/Th2 activation.10,35 Since Type 1/Th1immunity is considered to control viral responses, and there is a Th1/Th2 counter-regulation, we hypothesized that specific Th2 antagonism in patients with moderate-to-severe AD with the anti-IL-4Rα, dupilumab, may rebalance the Th1/Th2 axis, potentially leading to attenuated COVID-19 symptomatology.
Our study found that dupilumab reduces both the incidence and severity of COVID-19 symptoms among AD patients, compared to both other systemic treatments and to no systemic treatments. We found that patients treated with dupilumab were less likely to experience moderate-to-severe symptoms compared to patients on other systemics (p=0.01) as well as to patients on limited/no treatment (p=0.04). Patients treated with dupilumab were also less likely to experience any symptoms at all compared to patients on other systemics (p=0.01). This effect holds true for patients with suspected COVID-19, as well as for patients with a confirmed COVID-19 diagnosis or a confirmed high-risk exposure. Those treated with dupilumab were less likely to experience moderate-to-severe symptoms compared to those on other systemics (p=0.002) as well as on limited/no treatment (p=0.05) and were less likely to experience symptoms at all compared to patients on other systemics (p=0.03).
The robust effect of dupilumab on COVID-19 symptomatology may be due to primary modulation of Th2 pathway, without downregulation of Th1 immunity. This relationship between Th2 modulation and Th1/innate immune responses has been demonstrated in other atopic disease states, such as asthma.36 In one study, asthma patients treated with the Th2 modulator omalizumab (anti-IgE) had a lower incidence of respiratory virus-induced asthma exacerbations and a more robust IFNα response in vitro to rhinovirus stimulation.36Similarly, our study found that COVID-19 symptoms and severity were reduced in dupilumab even when compared to limited/no treatment, suggesting that Th2 suppression may normalize the Th1/Th2 imbalance Unlike dupilumab, broad acting immunosuppressants downregulate Th1 and other immune axes in addition to the pathogenic Th2 axis,23,37-39 which may account for the significant differences in clinical outcomes as compared to dupilumab, which reduces incidence and severity of symptoms in COVID-19. These results hold even when adjusting for a number of clinical and demographic variables that may affect COVID-19 severity, including race, age, and BMI.32 Older age and higher BMI were significantly associated with more frequent and more severe symptoms, consistent with prior knowledge.32
The main analysis in our study included all patients with a likely COVID-19 diagnosis, regardless of a laboratory-confirmed COVID-19 diagnosis. Thus, we acknowledge that some patients who reported probable COVID-19 symptoms may have had other infections (e.g. respiratory or gastrointestinal). However, we believe that this approach is crucial for several reasons: primarily, because there are likely many COVID-19 cases undiagnosed by formal testing in our cohort; testing was unreliable early on, and even now laboratory screening for asymptomatic cases is not routinely performed. Further, including all subjects may contribute to eliminating biases in testing behavior, since symptomatic patients are more likely to get tested. Additionally, although the impetus for this study was to evaluate the impact of immunomodulatory drugs specifically on COVID-19 symptomatology, these data showing that Th2 modulation potentially ameliorates COVID-19 symptoms extends beyond the current era. Our findings may thus have implications for other common viral infections, such as influenza, and for possible future pandemics.
In the setting of the current COVID-19 pandemic, despite the advent of vaccination and increasing efforts to widely distribute vaccines to the population, it remains crucial to understand the impact of immunomodulatory medications in patients with chronic inflammatory diseases; many people may be unable or unwilling to get vaccines, the long-term protection offered by vaccines is still unknown, and the efficacy and duration of immune response to vaccination in the setting of immunomodulatory medications remains unknown. Because of this, we also performed an analysis focused on outcomes in patients with confirmed laboratory evidence of COVID-19 infection or with significant known COVID-19 exposures, and the results in this subset were even more significant than those found in the entire cohort.
We acknowledge some limitations in this study. Primarily, there are inherent limitations to a registry-based study, including sampling bias, recall bias, and patients being enrolled at a single timepoint. Our study was also limited by the fact that we could not obtain laboratory confirmation (via serology testing) of COVID-19 infection in many patients. Additional testing will provide even more evidence for the relevance of these findings to confirmed COVID-19 infection.
Future studies are needed to understand the implications of our findings for other specific viral conditions. Furthermore, biomarker-based studies may provide added support for the proposed mechanism by which Th2 blockade might produce the results seen in this study. Additionally, understanding the immune response to COVID-19 vaccination in patients on immunomodulatory medications will be crucial as vaccination becomes increasingly widespread. Lastly, further studies in other inflammatory conditions commonly treated with immunomodulatory medications will be needed as well. The present study is the first to demonstrate the significant protection potentially offered by Th2-targeting with dupilumab in reducing symptom incidence and severity compared to other treatments for AD in the context of COVID-19 infection. These findings have important implications, not only for the millions of moderate-to-severe AD patients in this country exposed to COVID-19 and other viral infections, but potentially for patients with chronic atopic and other conditions on immunomodulatory medications.